Are You Confident of the Diagnosis?

What you should be alert for in the history

Familial Mediterranean Fever (FMF) is a monogenetic autoinflammatory disease that is characterized by periodic fevers and multisystemic inflammation. The diagnosis is frequently made clinically in countries where the disease is relatively common, although additional genetic testing is useful for confirmation. The populations affected tend to originate from the Mediterranean, Middle East, and North Africa.

Patients present in childhood with episodic bouts of fever, typically accompanied by abdominal pain (peritonitis). These episodes tend to last from 1-3 days, although rarely may last longer. Attack frequency is variable, with some patients experiencing weekly episodes and others experiencing them much less frequently (less than one per year). Although most attacks seem to occur without an obvious precipitating factor, they may be associated with stress, strenuous physical activity, or menstruation.

As FMF affects serosal surfaces, pleuritis, pericarditis, and arthritis may also accompany attacks. The characteristic skin eruption (the so-called “erysipelas-like erythema” [ELE]) is a much less frequent manifestation of FMF, affecting 15%-40% of the populations surveyed. There are also other reports of urticaria, purpura, angioneurotic edema, Raynaud’s phenomenon, pyoderma gangrenosum, and subcutaneous nodules.

Characteristic findings on physical examination

The musculoskeletal involvement is often monoarticular (frequently the large joints of the lower limb), presenting as an acute arthritis with erythema, warmth, tenderness, and swelling. ELE presents as tender warm erythematous well-demarcated plaques, usually on the lower legs or feet, as seen in Figure 1. These last for 2-3 days. Occasionally, boys can present with a unilateral tender scrotal swelling due to inflammation of the tunica vaginalis, which can clinically mimic torsion of the testis.

Figure 1.

Erysipelas-like erythema (ELE), seen in a patient with familial Mediterranean fever.

Expected results of diagnostic studies

ELE does not typically show vasculitic changes, although patients are at higher risk of getting purpura, independent of ELE. Synovial fluid is sterile with many neutrophils. Acute phase reactants such as C-reactive protein (CRP) and serum amyloid A (SAA) tend to be markedly elevated during an attack.

Diagnosis confirmation

Diagnosis is confirmed by genetic analysis. The differential diagnosis is wide when one considers recurrent fever of unknown origin; therefore, it is appropriate to consider occult infection or malignancy, or another inflammatory process, such as sarcoidosis. However, fever with recurrent serositis in a genetically susceptible population is highly suggestive of FMF.

Who is at Risk for Developing this Disease?

The disease is more prevalent among populations surrounding the Mediterranean Sea and the Middle East. It affects Turks, Armenians, Arabs, and non-Ashkenazi Jews. It has been estimated that the frequency is between 1:400-1:1000 in Turkey, 1:1000 in Israel, and 1:500 in Armenia. There have been no formal large-scale epidemiology studies to estimate worldwide prevalence, but probably fewer than 200,000 are affected.

What is the Cause of the Disease?

Etiology

FMF is an autosomal recessive disorder, resulting from mutations in the MEFV gene. FMF carrier frequencies are extremely high in the eastern Mediterranean.

Pathophysiology

MEFV encodes a protein called pyrin. Wild-type pyrin appears to have an important role in the regulation of the pro-inflammatory pathways of the innate immune system. Critically, it appears to modify the interleukin-1 (IL-1) family of cytokines. When both copies of MEFV are mutated, this results in uncurbed inflammation, explaining the clinical phenotype.

Systemic Implications and Complications

SAA is an acute phase reactant that is elevated during attacks of FMF, but can also persist at elevated levels between attacks. This persistant elevation of SAA can lead to systemic amyloidosis (AA). Certain mutations in MEFV, such as p.M694V, p.M694I, or p.M680I, portend a worse prognosis and a greater risk for amyloidosis.

Environmental factors also have a role in the development of amyloidosis; it has been observed that Armenian FMF patients have a much higher incidence of amyloidoisis than Armenian patients in the United States. It has also been observed that Turkish patients in Turkey have a higher incidence of amyloidoisis than Turkish patients in Germany. The amyloidosis frequently manifests itself as renal deposition, leading to end-stage renal failure.

Evaluation of patients with regard to amyloidosis should be directed towards assessment of renal status, as this is the main sequelae of systemic amyloidosis. Where available, measurement of serum amyloid in the serum should be done regularly. This test is not commercially available in the United States; however, measurement of CRP at least gives an indication of levels of inflammation in the patient.

Urinalysis should be performed regularly to look for proteinuria. Assessment of renal function, such as blood urea nitrogen (BUN) and creatinine, is important, as is a 24-hour urine collection, to calculate creatinine clearance. Abnormal renal function should be evaluated by a nephrologist. Renal biopsy may show amyloid deposition.

Treatment Options

Colchicine is indicated for both acute attacks and long-term maintenance. It is not completely understood why colchicine is an effective therapy for FMF, although it is thought to modulate microtubules in neutrophils, thereby preventing neutrophilic chemotaxis. It is extremely effective at preventing amyloidosis, which has now become much rarer in FMF.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used for acute musculoskeletal pain.

There is no specific treatment for the cutaneous manifestations of FMF.

Optimal Therapeutic Approach for this Disease

Typically, FMF patients are under the care of rheumatologists rather than dermatologists.

First-line therapy for FMF is colchicine. Dosing is 0.6mg or 0.5mg twice daily (depending on dosage form available). This is for long-term maintenance, to prevent acute attacks, and for the prevention of systemic amyloidosis.

As different populations with FMF have different relative risks for development of amyloidosis, it may be appropriate to target patients with high risk, such as Armenian patients in Armenia, Turkish patients, and North African Jews, For long-term therapy. or patients with much lower risk, such as Ashkenazi Jews and Armenians living in the United States, it may be appropriate to offer intermittent therapy, just to control acute attacks.

In patients for whom twice daily dosing is ineffective, the dosing frequency can be increased to three or four times daily, as tolerated by the patient. In cases recalcitrant to oral therapy, intravenous administration of colchicine (1mg per week) may be beneficial. Case reports have shown that interferon alpha, etanercept, infliximab, and anakinra may be helpful in patients who are intolerant of colchicine, or for whom it is ineffective.

Patient Management

Patients should be seen frequently when first diagnosed and when therapy is initiated. This typically would be every few weeks for the first couple of months. When patients are stabilized and attacks have become infrequent, follow-up frequency may be reduced to every 3-6 months.

Monitoring laboratory tests include complete blood count (CBC), renal function (including BUN and creatinine), liver function, CRP, and urinalysis (to check for presence of proteinuria). If patients have persistent inflammation, renal abnormalities, or proteinuria, they should be referred to nephrology.

Colchicine, either twice daily or intermittently for acute attacks, is the mainstay of therapy. Therapy should be altered if colchicine is not tolerated due to side effects (i.e. abdominal pain, nausea, vomiting, fatigue, headache, etc.). Rarely, bone marrow suppression, myopathy, rhabdomyolysis, nephrotoxicity, hepatotoxicity, or hypersensitivity reactions have been reported. Although colchicine is generally an effective therapy for FMF, other agents, such as interferon alpha, etanercept, and anakinra, have been reported to be helpful.

The key information that must be relayed to patients and families is that FMF is an autosomal recessive condition. Therefore, patients with FMF will pass on a mutated copy of the MEFV gene to offspring, but children will only be affected if they have also inherited a mutated MEFV gene from the other parent. It is important to emphasize that patients should be under regular follow-up, even if symptoms are well controlled, so that they can be monitored closely for any signs of amyloidosis.

The prognosis has become very good since the introduction of colchicine for FMF. Genetic testing is generally recommended for symptomatic individuals, rather than asymptomatic first-degree relatives. The key take-home message is that, since the introduction of colchicine, the prognosis for patients with FMF is excellent.

Unusual Clinical Scenarios to Consider in Patient Management

There is an association of Henoch-Schonlein purpura and polyarteritis nodosa with FMF. Also, Behçet's syndrome may be more common in FMF, although the same populations are at risk for both these diseases. It is very unusual for patients to have their first inflammatory episode in adulthood. There appears to be a clinical association between ankylosing spondylitis and FMF.

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